Squalene synthetase is a microsomal enzyme which catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate (FPP) in the presence of nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH) to form squalene (Poulter, C. D.; Rilling, H. C., in "Biosynthesis of Isoprenoid Compounds", Vol. I, Chapter 8, pp. 413-441, J. Wiley and Sons, 1981, and references therein). This enzyme is the first committed step of the de novo cholesterol biosynthetic pathway. The selective inhibition of this step should allow the essential pathways to isopentenyl tRNA, ubiquinone, and dolichol to proceed unimpeded. Squalene synthetase along with HMG-CoA reductase have been shown to be down-regulated by receptor mediated LDL uptake (Faust, J. R.; Goldstein, J. L.; Brown, M. S. Proc. Nat. Acad. Sci. U.S.A. 1979, 76, 5018-5022), lending credence to the proposal that inhibiting squalene synthetase will lead to an up-regulation of LDL receptor levels, as has been demonstrated for HMG-CoA reductase, and thus ultimately should be useful for the treatment and prevention of hypercholesterolemia and atherosclerosis.
European Patent Publication 0409181A3 discloses phosphorus-containing compounds which are inhibitors of cholesterol biosynthesis (by inhibiting de novo squalene biosynthesis), and thus are useful as hypocholesterolemic agents and antiatherosclerotic agents, which have the structure ##STR2## wherein m is 1, 2 or 3; n is 0, 1, 2, or 3;
Y.sup.1 and Y.sup.2 are H or halogen; PA1 R.sup.2, R.sup.3 and R.sup.4 may be the same or different and are independently H, metal ion, C.sub.1 to C.sub.8 alkyl or C.sub.3 to C.sub.12 alkenyl; PA1 X is 0, S, NH or NCH.sub.2 R.sup.15 wherein R.sup.15 is H or C.sub.1 to C.sub.5 alkyl; and PA1 R.sup.1 is R.sup.5 --Q.sup.1 --Q.sup.2 --Q.sup.3 -- wherein Q.sup.1, Q.sup.2 and Q.sup.3 are the same or different and are independently ##STR3## a single bond, with the proviso that if Q.sup.1 is a bond, then Q.sup.2 and Q.sup.3 are bonds and if Q.sup.2 is a bond, then Q.sup.3 is a bond, and wherein R.sup.6 is H, alkyl, halo, or haloalkyl; R.sup.7 is H, halo, alkyl or alkylthio; R.sup.8 is H, halogen, trimethylsilyl or lower alkyl; R.sup.9 is H or lower alkyl-; ##STR4## R.sup.16 --C.tbd.C--CH.sub.2 -- (wherein R.sup.16 is H or lower alkyl) or CH.sub.3 (CH.sub.2).sub.p where p is an integer from 2 to 7; R.sup.10, and R.sup.11 are the same or different and are independently H, lower alkyl, halogen, haloalkyl or lower alkenyl or R.sup.10 and R.sup.11 can be taken together to form (CH.sub.2).sub.s where s is an integer from 2 to 7; and R.sup.13 and R.sup.14 are the same or different and are independently lower alkyl, with the proviso that if all of Q.sup.1, Q.sup.2 and Q.sup.3 are bonds, then both R.sup.10 and R.sup.11 cannot be H and R.sup.5 cannot be alkyl(CH.sub.2).sub.p -- with p.ltoreq.4; including all stereoisomers thereof. PA1 X is --O--, --NH--, or --NR.sup.4 --; PA1 R, R.sup.1 and R.sup.1a may be the same or different and are H, lower alkyl, lower alkenyl or a metal ion; PA1 R.sup.2 and R.sup.3 may be the same or different and are H or halogen; PA1 R.sup.4 is lower alkyl; PA1 wherein n is 1 to 5; p is 0, 1 or 2; m is 0, 1 or 2; PA1 R, R.sup.1 and R.sup.1a may be the same or different and are H, lower alkyl or a metal ion; and PA1 R.sup.2 and R.sup.3 may be the same or different and are H or halogen. PA1 R.sup.40 =H, alkyl, cycloalkyl, or aryl such as methyl, ethyl, isopropyl, pentyl, phenyl and cyclopentyl PA1 R.sup.41 =alkyl such as methyl, ethyl or halo such as Cl or F ##STR54## PA1 R.sup.2 =H, metal ion or alkyl PA1 R.sup.3 =H, metal ion or alkyl PA1 R.sup.4 =H, metal ion or alkyl ##STR57## x.sup.1 =--(CH.sub.2).sub.n --, --CH.dbd.CH--CH.sub.2 -- n=2, 5
European Patent Publication 0356866A2 discloses phosphorus-containing compounds which inhibit the enzyme squalene synthetase and thus are useful as hypocholesterolemic agents and have the following structure ##STR5## wherein Q is ##STR6## or a bond; n is 1, 2, 3 or 4;
with the proviso that when X is 0, n is 2, 3 or 4.
U.S. Pat. No. 4,871,721 to Biller et al. discloses phosphorus-containing compounds which inhibit the enzyme squalene synthetase and thus are useful as hypocholesterolemic agents and have the following structure ##STR7## wherein Q is ##STR8## or a bond; Z is --(CH.sub.2).sub.n -- or --(CH.sub.2).sub.p --CH.dbd.CH--(CH.sub.2).sub.m -,
European Patent Application 0298553 A1 discloses bone active methylene phosphonoalkylphosphinic acids, and the pharmaceutically-acceptable salts and esters thereof, having the general structure: ##STR9##
R can be H or substituted or unsubstituted alkyl, each of A and B can be H as well as substituted or unsubstituted alkyl as well as other groups as disclosed. However, EP 0298553 A1 does not disclose how to prepare compounds where R is H.
Japanese Patent 50095227 (1975) to Sakurai et al. discloses compounds of the structure ##STR10## wherein R.sup.1 is H or alkyl, and R.sup.2 and R.sup.3 are alkyl or aryl, which are prepared by reacting amide ##STR11## with phosphorus trichloride.
Prishchenko et al., and Novikova, et al., Zh. Obsch. Khim., 1977, 47, 2689-2698 disclose the following reactions: ##STR12## R, R', R"=alkyl, Oalkyl, Nalkyl.sub.2